Degeneration and/or death of cells in the nervous system are major factors in many diseases and medical conditions. Such diseases and conditions include traumatic brain and spinal cord injuries, stroke, neural perfusion secondary to cardiac arterial bypass graft surgery (CABG), Parkinson's disease, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis and other neurodegenerative diseases. It is of interest to prevent or decrease such cell death and degeneration.
Certain compounds are useful as neuroprotective agents. One such compound is insulin-like growth factor 1 (IGF-1) (Scheepens et al., WO00/13650). IGF-1 is a naturally occurring peptide that can decrease the binding of glutamate to the glutamate receptors of neurons (Bourguinon, U.S. Pat. No. 5,804,550). IGF-1 can also decrease neuronal degradation caused by damage and disease. IGF-1 is cleaved by proteolysis in vivo to give des1-3 IGF-1 and the N-terminal tripeptide Gly-Pro-Glu (GPE). GPE and analogues have been found to be neuroprotective (Gluckinan et al., U.S. Pat. No. 6,187,906 incorporated herein by reference).
However, such peptides are far from ideal for the treatment of neural death and degeneration especially as they are rapidly metabolised in vivo. There is a need for compounds that provide neuroprotective and neuroregenerative properties and are more metabolically stable especially as regards resistance to proteases.
A derivative of GPE; cyclic Pro-Gly (“cPG”), a diketopiperazine, has been shown to be neuroprotective and neuroregenerative. cPG was found to prevent toxic neural degeneration and cell death and to promote neurite outgrowth in neurons (Guan et al., PCT/US02/36235 incorporated herein by reference). Diketopiperazine analogues of thyrotropin-releasing hormone (TRH) are known to be neuroprotective (Kozikowski et al. WO99/40931).